The ACR also recommends that patients who have not met targeted control of their disease on oral methotrexate be switched to subcutaneous methotrexate rather than another DMARD. A prior ACR guideline recommended escalating to triple therapy (i.e., methotrexate, sulfasalazine and hydroxychloroquine) for patients not at target on oral methotrexate.3 However, the 2021 guideline conditionally recommends adding a biologic DMARD or targeted synthetic DMARD over triple therapy for patients on the maximum methotrexate dose who are still not at target.
Drug Safety
Dr. Bingham also addressed drug safety issues, specifically related to Janus kinase (JAK) inhibitors. The ORAL Surveillance study is a clinical trial that enrolled patients aged 50 and older with moderate to severe RA and one or more cardiac risk factor for whom methotrexate proved inadequate. The study excluded patients with current or prior malignancy. The patients were divided into one of three clinical arms: 5 mg of tofacitinib given twice daily plus methotrexate; 10 mg of tofacitinib given twice daily plus methotrexate; however, after the drug safety monitoring review, this dose was lowered to 5 mg given twice daily; or a tumor necrosis factor-α (TNF) inhibitor plus methotrexate.4
The study demonstrated that tofacitinib combined with methotrexate was not non-inferior to TNF inhibitors plus methotrexate. Specifically, the number needed to harm for major adverse cardiac events over one year would be 567 for 5 mg of tofacitinib taken twice daily and 319 for 10 mg of tofacitinib taken twice daily.4
Dr. Bingham noted that independent risk factors for major adverse cardiac events included current smoking, aspirin use, being 65 years or older, and being male. Moreover, he stated that the highest rates of major adverse cardiac events were seen in patients with coronary artery disease and in patients with a high risk of major adverse cardiac events based on traditional risk factors.5 Thus, Dr. Bingham advocated for the use of an atherosclerotic cardiovascular disease (ASCVD) risk calculator, such as that available through the website of the American College of Cardiology, to assess which patients may or may not be good candidates for treatment with JAK inhibitors.
Regarding malignancy, lung cancer was the most frequently seen cancer in the ORAL Surveillance study, with independent risk factors of being age 65 years or older and current or past smoking. Interestingly, data indicate that non-melanoma skin cancer risk may be increased with methotrexate use. Thus, Dr. Bingham noted that patients on any form of DMARD therapy may be well served by an annual skin exam with a dermatologist. Finally, venous thromboembolism and pulmonary embolism were found to be an increased risk only in patients on the higher dose of tofacitinib.6
